Alkenes are fundamental chemical feedstocks used on massive industrial scales. Plotkin, J. S. Catal. Today (2005), 106, 10-14. The alkene functional group is important to fine chemical synthesis (e.g., synthesizing pharmaceuticals or other high value compounds), including multistep natural product synthesis. Otsuka, S.; Tani, K. In Transition Metals for Organic Synthesis (2nd Edition); Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, (2004); Vol. 1, p 199-209. The ability to control the formation and chemistry of alkenes is of central importance to organic synthesis in both industry and academia.
Alkene isomerization has been studied extensively in the literature. An examination of SciFinder revealed 6,405 hits using the search term “alkene isomerization” (7 Nov. 2013). Notwithstanding all the research and development of alkene syntheses, there remains a need today to better control both regiochemistry and stereochemistry of the alkene, particularly in the case of converting a 1-alkene to a trans-2-alkene, without either forming the cis-2-alkene or isomerizing further down the chain. The challenge is especially acute and unmet when the alkene contains no branching or substituents to control over isomerization. What one would like to have is a similar degree of control as that demanded and achieved routinely in asymmetric synthesis, where many reactions are optimized to exceed 90% e.e., corresponding to a product ratio of >20 to 1. Walsh, P. J., Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Mill Valley, Calif., (2009); Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis; Springer-Verlag: Berlin, (1999).
For example, one known alkene isomerization catalyst is selective for making and reacting with trans alkenes from terminal alkenes, but it is so active that it would not stop after one isomerization, unless the structure of the alkene substrate was such that the catalyst was impeded (a situation known as substrate control). What is needed is a new catalyst to control the reaction even in the case of a terminal alkene without special structural features.
In the more challenging case of unbranched alkenes or alkenes with remote branching, several known alkene isomerization catalysts have succeeded at regiocontrol at a >20 to 1 level, but did not offer significant stereocontrol, giving E/Z ratios in the range of 2 to 5, which essentially amounts to only thermodynamic control by substrate. Conventional catalysts that manage to achieve regiocontrol generally suffer from a lack of stereocontrol, and in most cases, are used at greater loadings or significantly higher temperatures. Veige's Cr(NCN)-pincer complex (10 mol %) offers some selectivity of 2-alkenes versus 3-alkenes (for hexene 95:5, octene 88:12) over 48 h at 85° C., however, the product cis:trans ratios were not specified. McGowan et al., Organometallics (2011), 30, 4949-4957.
Full conversion of 1-alkenes to 2-alkenes occurred using an unknown amount of Ru3(CO)12 as a catalyst provided a cis:trans ratio of product 2-octenes of 86:14. Sivaramakrishna et al., Polyhedron (2008), 27, 1911-1916. Recently, the isomerization of 1-octene to 2-octene (E/Z=65:26) has been reported, with small amounts of 3- and 4-octene, using a bulky Ir pincer complex (1 mol %) in 24 hours at high temperatures of 150° C., where NaOtBu was required as an additive. Chianese et al., Organometallics (2012), 31, 7359-7367. A slightly higher selectivity for the trans-2-alkene was observed using Fe(acac)3 (5 mol %) in 10 hours at RT, where 50 mol % PhMgBr as additive was required, affording 97% 2-octene (E/Z=5:1, essentially the thermodynamic E/Z ratio), in addition to 3-alkene and unreacted starting 1-octene. Mayer et al., ChemCatChem (2011), 3, 1567-1571. Another study isomerized 1-hexene using Ru(CO)3(PPh3)2 (0.5 mol %) to form 80% 2-hexene (E/Z=2:1) and 16% 3-hexene in 3 h at 40° C. Krompeic, S.; Suwinski, J.; Grobelny, J. Pol. J. Chem. (1996), 70, 813-818. Yet another study used Fe3(CO)12 (1 mol %) and 3 N KOH at 80° C. on 1-octene to make 96% 2-octene (E/Z=3.1:1). Jennerjahn et al., ChemSusChem (2012), 5, 734-739.
Although several of the known catalysts gave high positional selectivity, none of them deviated significantly from the thermodynamic E:Z ratio of about 4 to 1, and generally suffered from further isomerization of the 2- to the 3-alkene. One of the more selective conventional protocols used 50° C. and a Co—NHC complex (5 mol %), which generated in situ, giving 81% 2-tetradecene (E/Z=40:1) and 2% 3-alkene, in addition to 3% of 1-alkene. Kobayashi, T.; Yorimitsu, H.; Oshima, K. Chem. Asian J. (2009), 4, 1078-1083. The (E)-selectivity makes these results stand above other catalyst systems, but required the use of a specialized Grignard reagent (Me2PhSiCH2MgCl, 50-100 mol %) to form the selective catalyst, which is incompatible with many functional groups; for example, a normal benzoic acid ester was not suitable, and 2-alkene selectivity was eroded in some cases by polar substituents.
Our previously reported “alkene zipper” catalyst 2a does not generally solve the problem of simultaneous positional and geometric isomer control. (a) Grotjahn, D. B.; Larsen, C. R.; Gustafson, J. L.; Nair, R.; Sharma, A. J. Am. Chem. Soc. (2007), 129, 9592-9593; (b) Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. (2012), 134, 10357-10360. Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. (2012), 134, 15604; (c) Erdogan, G.; Grotjahn, D. B. J. Am. Chem. Soc. (2009), 131, 10354-10355; (d) Erdogan, G.; Ph.D. Thesis, Univ. of California at San Diego and San Diego State Univ. (2012). This catalyst system required substrate modifications, such as branching or the use of certain functional groups (e.g., an alcohol protecting group), to engineer the reaction conditions to achieve monoisomerization. In addition, many branched substrates cannot be selectively monoisomerized with catalyst 2a. Moreover, catalyst 2a is too active for the monoisomerization of non-functionalized, simple hydrocarbon alkenes, like 1-heptene, and the result is a mixture of trans-alkene isomer products. Finally, increasing the bulk of substituents on the phosphine ligand in 2a while keeping the cyclopentadienyl ligand constant were not successful in creating a catalyst capable of simultaneous positional and geometric isomer control. Erdogan, G.; Ph.D. Thesis, Univ. of California at San Diego and San Diego State Univ. (2012).
Other publications disclose substituted and unsubstituted cyclopentadienyl catalysts, but none of them, alone or together, teach a catalyst that can provide simultaneous positional and geometric isomer control. See e.g., US 2014/0228579 (Nikonov et al.), Method For The Catalytic Reduction Of Acid Chlorides And Imidoyl Chlorides; Machin et al., Org. Lett. (2009), 11(10), 2077-2080, Ruthenium-Catalyzed Nucleophilic Ring-Opening Reactions of a 3-Aza-2-oxabicyclo[2.2.1]hept-5-ene with Alcohols; Varela et al., J. Am. Chem. Soc. (2006), 9576-9577, Ru-Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes; Yamamoto et al., Org. Lett. (2014), 16, 1806-1809, Tandem Ruthenium-Catalyzed Transfer-Hydrogenative Cyclization/Intramolecular Diels-Alder Reaction of Enediynes Affording Dihydrocoumarin-Fused Polycycles; and Severa et al., Tetrahedron Lett. (2009), Vol. 50, 4526-4528, Air-tolerant C—C bond formation via organometallic ruthenium catalysis: diverse catalytic pathways involving (C5Me5)Ru or (C5H5)Ru are robust to molecular oxygen. Moreover the above-mentioned publications do not teach that there are significant differences in product yields when substituted and unsubstituted cyclopentadienyl catalysts are used.
Thus, new catalysts and methods that are fast and efficient are needed to overcome the dual challenges of controlling the position of the double bond in a molecule, and controlling molecular shape in the form of cis/trans-selectivity in isomerization of terminal alkenes to their 2-isomers. A suitable catalyst would minimize or avoid thermodynamic equilibration of alkene isomers, for example, to provide trans-2-alkenes, of both non-functionalized and functionalized alkenes.